The regulation of gamma-globin gene expression.
In summary, our analysis indicates that important sequences for the proper initiation of fetal gene transcription in fetal cells are located in the gamma-globin [sequence: see text] promoter. These sequences are sufficient for tissue-specific expression but not induction in K562 cells. Sequences in the gamma-globin IVS-2 and the beta-globin 3' enhancer increase gamma beta and gamma-Neo transcripts when cells containing these genes undergo erythroid maturation as measured by induction with hemin. The mechanism by which these sequences exert their effect remains to be elucidated. [see text] Multiple protein factors bind to both the gamma promoter and the beta 3' enhancer. Both of these regions contain binding sites for the erythroid-specific factor NFE-1 and the octamer binding factor OTF-1. In the gamma upstream region, there may be a competition between OTF-1 binding and NFE-1 binding that affects gamma gene regulation. Our results indicate that the beta 3' enhancer interacts with the gamma gene promoter to permit increased gamma gene expression. We have developed a model for globin gene switching that takes into consideration the effect of cis-acting sequences on globin gene transcription. A similar model of hemoglobin switching in chickens has been proposed by Choi and Engel. In our model, competition for the beta-globin 3' enhancer is involved in stage-specific transcriptional activation of gamma-globin genes in fetal cells and beta-globin genes in adult cells. In adult cells the protein-protein interactions between adult cell-specific factors interacting with the beta-globin promoter and erythroid-specific factors interacting with the beta 3' enhancer would activate transcription of the beta-globin gene. In fetal cells protein-protein interactions between fetal cell-specific factors interacting with the gamma-globin promoter and erythroid-specific factors interacting with the beta 3' enhancer would activate the transcription of the gamma-globin genes.
Donovan-Peluso
M
M
Department of Pathology, University of Pittsburgh, Pennsylvania 15261.
Acuto
S
S
O'Neill
D
D
Kaysen
J
J
Hom
A
A
Maggio
A
A
Bank
A
A
D001483:Base Sequence; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic
D011993:Recombinant Fusion Proteins; D005914:Globins